The Microbiome Conundrum, Part 1
Why is it so hard to show causality between the microbiome and immune system?
“Big data cannot yield complicated descriptions of causality. Especially in healthcare. Almost all of our diseases occur in the intersections of systems in the body.” —Clayton M. Christensen
The collection of microbes that colonize our colon—our microbiome—is a marvelous buffer against the ravages of nature. If we could guide those microbes and channel their energy, we might be able to prevent or cure dozens of inflammatory diseases. Shockingly, the diseases initiated by a poorly balanced set of microbes include arthritis, heart disease, diabetes, cancer, and dementia. These are some of the most intractable afflictions known to mankind.
But there is a feedback loop between gut microbes and inflammation that complicates an already challenging situation. We know that an unhealthy gut microbiome can cause systemic inflammation. But inflammation can also wipe out gut microbes, potentially making things worse.
The microbiomes of some unhealthy people seem to be unbalanced or “dysbiotic,” but no one really knows exactly what that means. Given our ignorance, how can we take advantage of the power of the microbiome?
Embracing Our Ignorance
What we do know is that the greater the microbial diversity, the less inflammation. It’s not much to go on, but it’s a start. It implies that we could encourage a healthy microbiome with a highly varied diet of fiber-filled veggies and fruit.
There may be some identifiable villains. Some bacterial families, such as Enterobacteriaceae, are found lurking in greater numbers in inflammatory conditions. This family includes such notables as Salmonella, E. coli, Shigella, Enterobacter, Citrobacter, and Klebsiella. Most of these have flagella, so they can swim to attractive targets, like the mucus that coats our gut from stem to stern. They also have fimbria, which are like tiny grappling hooks these microbes use to attach themselves to human cells. One other feature: They love sweets.
The outer membrane of these microbes is composed of fat and sugar. The fatty part is a lipid that helps to create the membrane, and the sugar part forms threads resembling cotton candy hair on the bacteria. This bacterial building block is called lipopolysaccharide (LPS) in honor of its two main components.
When one of these microbes dies, the membrane breaks up into LPS molecules that are well-known to the immune system. We have battled these microbes long enough to have LPS detection baked into our genes, as part of our innate immune system.
If you inject someone with LPS, within minutes, they will become highly anxious and run a fever. In sufficient doses, they will become septic. In lower doses, chronic exposure to LPS is associated with a host of diseases, including depression and anxiety.
So, we see that microbes can trigger an immune response. But that response can change the microbiome in unexpected ways. Next week, we’ll talk more about the sometimes tragic cycle of microbes and immunity.
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References
Walker, A.W., Hoyles, L. Human microbiome myths and misconceptions. Nat Microbiol 8, 1392–1396 (2023).
Patil, Abhinandan, and Neha Singh. “Microbiota Modulation: Examining the Effects on Pathogen Colonization and Infection.” Preprints, July 17, 2023.
Schneider, Tamar. “The Microbiome Function in a Host Organism: A Medical Puzzle or an Essential Ecological Environment?” Biological Theory, March 27, 2023.